Abstract
In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNF alpha-treated cells and which genes display an interaction effect between heteronemin and TNF alpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappa B (NF-kappa B) signaling cascade.
We confirmed in silico experiments regarding NF-kappa B inhibition by reporter gene analysis, electrophoretic mobility shift analysis and I-kappa B degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypsin-like proteasome activity at an IC50 of 0.4 mu M. Concomitant to the inhibition of the NF-kappa B pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by annexin V-FITC/propidium iodide-staining, nuclear morphology analysis, pro-caspase-3, -8 and -9 and poly(ADP-ribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, results show that this compound has potential as anti-inflammatory and anti-cancer agent.
Original language | English |
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Pages (from-to) | 610-622 |
Number of pages | 13 |
Journal | Biochemical Pharmacology |
Volume | 79 |
Issue number | 4 |
Early online date | 6 Oct 2009 |
DOIs | |
Publication status | Published - 15 Feb 2010 |
Keywords
- NF-kappa B
- marine natural product
- anti-cancer drug discovery
- marine natural-products
- cycle arrest
- signaling pathways
- microarray data
- down-regulation
- start sites
- cancer
- expression
- biology
- inflammation